This invention relates to a method of detecting colorectal adenomas and cancer, and in particular to a method of detecting such adenomas and cancer using proton magnetic resonance spectroscopy.
Colorectal cancer is one of the most common cancers in the U.S.A. and Canada accounting for approximately 146,000 new cases in 1999. The lifetime risk that an individual in North America will develop colorectal cancer is about 5-6%. Symptoms associated with colorectal cancer, including blood in the stool, anemia, abdominal pain and alteration of bowel habits often become apparent only when the disease has advanced significantly. It is well known that prognosis for a patient depends largely on the stage of the disease at the time of diagnosis. In fact, whereas the five-year survival for a patient whose colorectal cancer is detected at an early stage is 92%, survival decreases to about 60% in patients with regional spread, and to about 6% in those with distant metastasises. Accordingly, it is important to detect the precursor adenomas and cancer as early as possible to increase the chances of successful therapeutic intervention.
Screening for a disease requires that the disease be prevalent in a large segment of the population and that early detection of the disease decreases mortality and improves quality of life. Colorectal cancer meets these requirements and, thus, is an ideal candidate for such a program. The natural history of colorectal cancer, namely the progression from adenoma to adenocarcinoma occurring over a number of years (5-15), also makes it a suitable target. The cost benefit analysis for the early detection of colorectal cancer has also been shown to be favourable (Bolin, T D. Cost benefit of early diagnosis of colorectal cancer. Scand J Gastroenterol 1996; 31 Suppl 220:142-146).
The screening technique itself also has to meet a series of criteria, such as, high sensitivity and specificity, low cost, safety and simplicity. Currently, digital rectal examination (DRE), fecal occult blood test (FOBT), barium enema and direct colon visualization (sigmoidoscopy and colonoscopy) are used for this purpose.
DRE involves examining the rectum using a finger. This method detects cancers that can be palpated and are within reach of the finger. A negative DRE provides little reassurance that a patient is free of cancer, because fewer than 10% of colorectal cancers can be palpated by the examining finger.
FOBT detects hidden blood in the stool by chemical means on the assumption that all colorectal cancers bleed. Although the least expensive and the simplest, the FOBT method has low sensitivity, moderate specificity and is usually not good for early detection. According to available data, a major drawback of this technique is that more than half of the cancers discovered by this method followed by x-ray or endoscopy are usually beyond the limit of early staging. A false positive rate of 10-12% is expected when the patients tested are on an unrestricted diet. Estimates of the positive predictive value range from 2.2 to 50%. The guaiac tests have a very low sensitivity, generally around 50% (Ransohoff D F, Lang C A, Screening for colorectal cancer with the fecal occult blood test; a background paper. Ann Intern Med 1997; 126:811-822). The use of FOBT is based on the assumption that colorectal cancers are associated with bleeding. However, some colorectal cancers bleed intermittently and others not at all.
A barium enema involves an x-ray of the bowel using a contrast agent. The enema can be a single or double contrast. The main radiologic signs of malignancy include muscosal distraction, abrupt cut-off and shouldering and localized lesions with sharp demarcations from uninvolved areas. The estimated sensitivity of double contrast barium enema for cancer and large polyps is only about 65-75% and even lower for small adenomas. Despite its better diagnostic yield, double contrast barium enema has a false-negative rate of 2-18%. Moreover, the method involves exposure to radiation, the repeated use of which may not be safe. Perforation from barium enema is extremely uncommon, but when it happens it is frequently fatal or leads to serious long term problems as a result of barium spillage into the abdominal cavity.
A variety of instruments (collectively called endoscopes) are used for examining the bowel. Endoscopes can be rigid or flexible with varying lengths. Rigid sigmoidoscopes are usually 25 cm long while flexible sigmoidoscopes are 35 or 60 cm long. A colonoscope is a 130-160 cm flexible viewing instrument for examining the entire colon. Biopsies are taken from suspicious looking areas while viewing the colon through the endoscope. The flexible sigmoidoscopy examination is limited to the left side of the colon and rectum. Approximately ⅓ of neoplastic tumors occur in areas proximal to the splenic flexure that are inaccessible by sigmoidoscopy. Colonoscopy has a high sensitivity, and remains the gold standard for visualization of the colon and the detection of neoplastic abnormalities. However, it is invasive, quite expensive, and exposes the subject to risks of bowel perforation.
Magnetic resonance spectroscopy (MRS) is a technique that has the potential to detect small and early biochemical changes associated with disease processes, and has been proven to be useful in the study of tissue biopsies from cancer patients (Smith I C P, Bezabeh T. Tissue NMR ex vivo.In: Young I R, editor, Encyclopedia of NMR: Medical Spin-off Volume, In Press (2000)). It is particularly useful to detect small, mobile chemical species in a given biological sample that are of diagnostic interest. Obtaining tissue biopsies for such an examination, however, usually involves an invasive procedure.
There are a number of currently available methods for detecting cancer in its early stages. Biophysical methods such as conventional X-rays, nuclear medicine, rectilinear scanners, ultrasound, CAT and MRI all play an important role in early detection and treatment of cancer. Clinical laboratory testing for tumor markers can also be used as an aid in early cancer detection. Tumor marker tests measure either tumor-associated antigens or other substances present in cancer patients which aid in diagnosis, staging, disease progression, monitoring response to therapy and detection of recurrent disease. Unfortunately, most tumor marker tests do not possess sufficient specificity to be used as screening tools in a cost-effective manner. Even highly specific tests suffer from poor predictive value, because the prevalence of a particular cancer is relatively low in the general population. The majority of available tumor marker tests are not useful in diagnosing cancer in symptomatic patients because elevated levels of markers are also seen in a variety of benign diseases. The main clinical value of tumor markers is in tumor staging, monitoring therapeutic responses, predicting patient outcomes and detecting recurrence of cancer.
U.S. Pat. Nos. 4,912,050 and 4,918,021, issued to E. T. Fossel on Mar. 27, 1990 and Apr. 17, 1990, respectively disclose a technique for detecting cancer by proton nuclear magnetic resonance (NMR) of blood, blood serum or blood plasma. U.S. Pat. No. 5,261,405, issued to the same inventor on Nov. 16, 1993 describes an apparatus and method for automating the process.
U.S. Pat. No. 5,318,031, issued to Mountford et al on Jun. 7, 1997 describes a method for determining chemical states of living animal or human tissue using NMR and 2D-COSY (two-dimensional correlation) NMR spectroscopy, and comparing measured values to reference measurements of normal, abnormal and transitions state tissue.
C. L. Lean et al (Magn. Reson Med 20:306-311, 1991; Biochemistry 3:11095-11105, 1992 and Magn Reson Med 30:525-533, 1992) describe the use of magnetic resonance spectroscopy to examine colon cells and tissue specimens.
However, a need still exists for an inexpensive, non-invasive method of detecting colorectal cancer and colorectal adenomas. The object of the present invention is to provide a relatively simple, non-invasive method of detecting colarectal adenomas and cancer which meets the above defined criteria of high sensitivity and specificity, low cost and safety.
Accordingly, the invention relates to a method of detecting the presence of colorectal adenomas and colorectal cancer in a patient comprising the steps of subjecting a liquid suspension of a stool sample from the patient to magnetic resonance spectroscopy; and comparing the resulting spectrum with the magnetic resonance spectra of stool from non-cancerous subjects, with observed differences in spectra being indicative of cancer.
The performing of spectral analysis on human stool offers a significant advantage over other methods, because the collection of the specimen is non-invasive and presents no risk to the patient. Moreover, no special processing of the sample is required prior to analysis.
The use of 2D-COSY spectroscopy is preferred, because while one-dimensional 1D MRS can give information on the nature and relative intensities of biochemical species present in a given sample, it does not always allow an exclusive and unambiguous identification of some of the species. Two dimensional MRS can be defined as a series of 1D MR spectra acquired with varying pulse delays, and subsequently Fourier-transformed along two axes (the acquisition time and the delay time). Such an approach allows the separation of composite 1D spectral resonances by generating cross-peaks in a second dimension, which identifies protons coupled together. The method makes it possible to detect species present in low concentrations, and normally masked in 1D spectra by other species present in larger concentrations.